Potassium channels play a central role in cardiac and neuronal functions. Mutations of the human ether-a-go-go (hERG) potassium channel are causal to long QT syndrome. Many drugs that have been withdrawn from the market are due to the inhibitory effects on potassium channels such as hERG, thereby causing prolongation of the QT interval, which ultimately could lead to cardiac sudden death. The failure to express a membrane receptor on a cell surface represents one of the most common and well known mechanisms of action that are caused by genetic mutations in human diseases, including the Long QT syndrome. Although the sequence motifs that dominantly localize protein to intracellular compartments (e.g., ER retention or localization) have been studied extensively, little is known about either motifs or machinery that zipcode the plasma membrane expression of surface receptors. The proposed research is focused on the biogenesis of potassium channel using a combination of molecular, biochemical, and electrophysiological approaches. This proposal is aimed at addressing fundamental questions concerning potassium channel biogenesis. By achieving the proposed goals, much will be learned about the forward trafficking process. This information may provide a general principle concerning functional expression of membrane proteins, and important insights into the molecular basis of human diseases.